Dennis K. Miller

Developmental Lead Exposure Alters the Stimulatory Properties of Cocaine at PND 30 and PND 90 in the Rat

The aim of this study was to examine the effects of perinatal lead exposure on locomotor responding following acute and repeated cocaine challenges (sensitization). Adult female rats were gavaged daily with 0, 8, or 16 mg lead acetate for 30 days prior to breeding. This exposure regimen was maintained throughout gestation and lactation (perinatal exposure). On Day 21, male pups were weaned and lead exposure was discontinued for the remainder of the study. Beginning on postnatal day (PND) 30 or PND 90, and continuing for 14 successive days, separate groups of perinatally-exposed animals were presented with challenges of 10 mg/kg cocaine HCl (i.p.), and tested for locomotor responding. Following this testing period, dose-effect profiles were determined, with animals receiving daily injections of 0, 10, 20, and 40 mg/kg cocaine. The results indicated that both at PND 30 and PND 90 lead-exposed animals were less responsive to the initial administration of cocaine, but exhibited a supersensitivity to the stimulatory effects associated with repeated administration of cocaine, i.e., behavioral sensitization to cocaine was augmented by perinatal lead exposure. Analyses of blood lead levels following the completion of testing revealed that lead levels were below detectable limits for all animals (< 1 μg/dl). Collectively, these findings show that developmental lead contamination produces changes in cocaine sensitivity long after exposure has been discontinued and the toxicant has gained clearance from blood.

Chronic cadmium exposure attenuates the conditioned reinforcing properties of morphine and fentanyl

Adult male rats were exposed ad libitum for 40 days to 100 ppm cadmium chloride through their diet, or an identical diet with no added cadmium. Conditioned place preference (CPP) was conducted in a 2-chamber apparatus in which all drugs were paired with the least-preferred side as determined on a pre-test. In Experiment 1. control and cadmium-exposed rats received 0, 0.6, 1.25, 2.5, or 5 mg/kg morphine sulfate (i.p.) for 4 days, and vehicle only for 4 days. Control animals showed a preference for the drug-paired side at 1.25, 2.5, and 5 mg/kg while the cadmium-exposed rats showed a preference at 5 mg/kg only. In Experiment 2, rats were implanted with cannulae into the lateral ventricles and 0, 2, 5 micrograms morphine sulfate was administered intracerebroventricularly (i.c.v.). An attenuation by cadmium again was observed, as control animals showed a place preference at 2 and 5 micrograms and cadmium-exposed animals showed preference at 5 micrograms only. In Experiment 3, increasing doses of the mu-opioid receptor agonist fentanyl (0, 0.0004, 0.004, and 0.04 mg/kg) were systemically administered (s.c.) and rats tested for CPP. While cadmium animals showed place preference only at 0.04 mg/kg, control animals showed preference at 0.0004, 0.004, and 0.04 mg/kg. These findings are discussed within the framework of metal-induced disturbance of neurochemical function and/or associative processing, and the implications that such disturbances may have for drug seeking and taking.

Differential effects of adult and perinatal lead exposure on morphine-induced locomotor activity in rats.

The effects of adult and perinatal lead treatment on the development of locomotor sensitization produced with repeated morphine administration was investigated. In Experiment 1, adult male rats received a diet containing 250 ppm lead acetate or a control diet for 43 days. Animals then received 10 mg/kg morphine sulfate or water vehicle (ip) and locomotor activity was monitored for 14 consecutive days. While both control and lead-exposed animals demonstrated a locomotor sensitization to morphine, the magnitude of the increased locomotor response was reduced in lead-treated animals. Subsequent analysis of blood-lead in the adult lead-exposed animals indicated residue levels ranging between 20 and 30 microg/dl. In Experiment 2, adult female rats were treated daily with 0, 8, or 16 mg lead via gavage for 30 days before breeding with non-exposed males. Lead exposure in dams continued through gestation and until pups were weaned at postnatal day (PND) 21. At PND 60, male offspring received morphine or vehicle challenges identical to those described in Experiment 1. Animals perinatally exposed to dams receiving 16 mg lead daily demonstrated an enhanced behavioral response to morphine relative to control animals. Analysis of offspring blood indicated lead levels below detectable limits (<1 microg/dl) for all animals. The results suggest exposure to lead at environmentally relevant levels produces long-lasting changes in drug-induced behavior, and the developmental period in which lead exposure occurs is a significant contributor to the manifestation of these effects.

Brain and plasma levels of cocaine and benzoylecgonine in lead-exposed and cadmium-exposed rats following acute or chronic intraperitoneal administration of cocaine

Previous investigations of metal/cocaine interactions have shown that chronic oral exposure to inorganic lead or cadmium attenuates the psychoactive effects of acute or repeated administration of cocaine. The purpose of this investigation was to assess the possibility that such interactive effects may derive from metal-induced disturbances in cocaine pharmacokinetics, i.e., delivery of cocaine to critical biologic sites may be disrupted by metal contamination. In this study, adult male rats were exposed to purified diets containing 250 ppm lead acetate (Group Lead), 100 ppm cadmium chloride (Group Cadmium), or unadulterated laboratory chow (Group Control); n = 48/exposure condition. Following ad libitum access to their respective diets in the home cage for 45 days, half the animals from each exposure regimen received single daily IP injections of 5, 10, or 20 mg/kg cocaine HCl for a period of 7 days (n = 8/group). The remaining half the animals received repeated daily injections of saline during this pretreatment phase. On the day following pretreatment, animals previously receiving cocaine injections were administered a single cocaine test challenge at a dose equal to that received in pretreatment. Similarly, saline pretreatment animals received either 5, 10, or 20 mg/kg cocaine. The results of this investigation did not reveal reliable evidence of metal-related differences in brain levels of cocaine. Plasma cocaine and benzoylecgonine (BE) levels also were essentially the same for control and metal-exposed animals. The failure to show that lead or cadmium alters the disposition of cocaine in brain or plasma underscores the need to pursue alternative accounts of metal/cocaine interactions.

Chronic cadmium exposure attenuates conditioned place preference produced by cocaine and other drugs.

Adult male rats were exposed ad lib for 40 days to 100 ppm dietary cadmium chloride (group cadmium) or an identical diet with no added cadmium (group control). Conditioned place preference (CPP) was conducted in a two-chamber apparatus in which all drugs were paired with the least-preferred side as determined by a pretest. In Experiment 1, animals received 0, 2.5, or 5 mg/kg cocaine HCl (IP) for 4 days and vehicle only for 4 days. Control animals showed a place preference for the drug side at 2.5 and 5 mg/kg, while the cadmium-exposed animals showed a preference at 5 mg/kg only. In Experiment 2, animals received 0, 5, or 10 mg/kg of the D1/D2 dopamine receptor agonist apomorphine HCl (SC) for 4 days and vehicle only for 4 days. Control animals showed a place preference at 5 and 10 mg/kg, while metal-exposed animals showed a preference at 10 mg/kg only. To determine the possible effects of alterations of learning mechanisms by cadmium, a conditioned place aversion (CPA) procedure was employed for Experiment 3. Animals received 0, 10, or 40 mg/kg lithium chloride (IP) for 4 days or vehicle only for 4 days. Control animals showed a significant place aversion at 40 mg/kg, while cadmium-exposed animals did not. These findings are discussed within a framework of possible metal-induced disturbance of neurochemical function and/or associative processing.

Sensitization of anorexia and locomotion induced by chronic administration of ephedrine in rats.

Repeated daily administration of the sympathomimetic agent ephedrine (EPH) leads to an augmentation (sensitization) of locomotor activity in rats. The present experiments examined the impact of repeated administration of the (-)- and (+)-EPH enantiomers on feeding in rats to assess whether the anorexic activity of EPH exhibits tolerance or sensitization during chronic exposure and whether the time course of these effects follows that observed in studies of locomotion. Adult male rats were injected once daily for 12 days with either vehicle or 5, 10 or 20 mg/kg (-)-EPH or with 10 or 20 mg/kg (+)-EPH. Horizontal locomotion and diet consumption were assessed for 60 min in an activity chamber. Suppression of feeding and the induction of locomotion were augmented over the first four days of administration of either 10 mg/kg or 20 mg/kg of the (-)-EPH enantiomer. In contrast, repeated administration of 20 mg/kg (+)-EPH resulted in augmentation of appetite suppression but not locomotion. These results confirm and extend the phenomenon of locomotor and feeding sensitization for ephedrine, but suggest that these effects may differ for the two enantiomers of ephedrine.

Repeated administration of ephedrine induces behavioral sensitization in rats

Abstract Systemic injection of the sympathomimetic agent ephedrine (EPH) stimulates locomotion in drug-naive rats, an effect that may be dependent on the enantiomer of EPH employed [(–)-EPH or (+)-EPH]. The present experiments examined the effects of repeated EPH exposure on locomotion in rats to assess whether these treatments result in drug tolerance or sensitization. In experiment 1, adult male rats were injected once daily with 0, 10, 20, or 40 mg/kg (–)-EPH (IP) on each of 11 days. Locomotor activity was assessed for 60 min after drug injection. Acute exposure to (–)-EPH treatment increased locomotion for animals receiving 20 or 40 mg/kg, and this effect was augmented after 11 days of drug administration. A vehicle-only injection was given to all animals on day 12 to determine the influence of environmental cues on sensitization. On day 13, all rats were injected with 10 mg/kg cocaine HCl to assess whether repeated (–)-EPH exposure produced a cross-sensitization to cocaine (10 mg/kg, IP). Only rats treated repeatedly with 40 mg/kg (–)-EPH exhibited increases in cocaine-stimulated locomotion relative to saline-treated rats. In experiment 2, repeated exposure to (+)-EPH, 40 mg/kg, but not 20 mg/kg, increased activity and demonstrated the development of sensitization. Cross-sensitization to cocaine (10 mg/kg, IP) was not evident following treatment with either concentration of (+)-EPH. There was no evidence that contextual events alone played a role in the effects observed here.

Chronic exposure to cadmium attenuates behavioral sensitization to morphine

Abstract The purpose of this investigation was to assess the impact of dietary cadmium on morphine-induced changes in locomotor activity. Adult male rats were exposed ad libitum to an adulterated food supply containing 100 ppm added cadmium chloride, or an identical diet containing no added cadmium, for 45 days prior to testing for the locomotor activating effects of successive daily morphine administration (0, 5,10, or 20 mg/kg per session) on locomotor activity. On day 1 of testing, increasing doses of morphine produced a dose-related suppression of activity, and this sedative effect was greater in control than in cadmium-exposed animals. Repeated morphine administration resulted in tolerance to the sedative effects of the drug, and a systematic elevation of locomotor activity over the 14-day testing period was observed, with the augmentation (sensitization) effect more pronounced in control than cadmium-exposed animals. There was no indication that conditioning (context) events played a role in the effects observed here.